Neurodegenerative diseases are characterised by a degradation or degeneration of nerves which are generally caused by apoptosis. Examples of neurodegenerative diseases include Alzheimer's disease, mild cognitive impairment, Parkinson's disease as well as AIDS-related neurological disorders. For example, in Alzheimer's disease, the nerve degradation leads to a disruption of the ability to remember, speak, think and make decisions. The reasons for these disorders are not known in detail. On the biochemical level, a change in the cortical cholinergic systems with a decrease in the formation of the neurotransmitter acetylcholine is detectable. In the cerebral cortex of patients suffering from Alzheimer's disease, the acetylcholine concentration is decreased by 20 to 40%. As a result thereof, nerve ends are attacked, and this leads ultimately to the death of the cerebral cells, particularly those of the hippocampus.
In light of these observations, therapeutic approaches for Alzheimer's disease therefore address the stabilisation of the acetylcholine concentration, particularly by inhibiting acetylcholine esterase which degrades acetylcholine to acetate and choline. However, the use of acetylcholine esterase inhibitors shows the drawback that this results in an only temporary improvement which is not suitable for stopping or even reversing the nerve degeneration.
On the other hand, so-called neurotrophic factors or neurotrophines are known to which a significant influence on the survival, growth and differentiation of discrete neuronal populations is ascribed. The neurotrophine family includes nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophine-3 (NT-3), neurotrophine-4 (NT-4) and the CNTF-family (ciliary neurotrophic factor). Neurotrophines are small basic proteins with a molecular weight of 26 to 28 kDa. NGF is the best characterised member of the neurotrophine family which shows activity in many different tissues.
In the peripheral nervous system (PNS) NGF is critical to the development of sympathetic and certain sensory nerves. In the central nervous system (CNS), NGF serves a trophic role in the development and maintenance of cholinergic neurons of the basal forebrain. It also plays a role in adult CNS tissues in neuronal regeneration.
It is known that cholinergic neurons produce acetylcholine in the presence of NGF rather than in its absence. Moreover, it has also been demonstrated that the administration of NGF to primates leads to the regeneration of cholinergic cell bodies. Based on this finding it is assumed that an altered activity of NGF may thus be a starting point for the degeneration of cholinergic neurons. At least theoretically it thus appears that neurotrophic substances are suitable for the treatment of neurodegenerative diseases such as Alzheimer's disease. However, these physiologically occurring substances have a short action radius similar to autocrine or paracrine substances. Therefore it is until today not possible to use common therapeutical routes (enteral or parenteral) for their application, as they are processed proteolytically in the blood circulation and other tissues and are thereby inactivated. Besides, it is known that they do not pass the blood-brain barrier (BBB) which is a prerequisite of CNS activity.
Clinical trials carried out with recombinant human neurotrophines have failed so far. A conceivable intracerebral administration should be excluded by practical consideration. Therefore, a transfer of results from in vitro experiments with NGF or other neurotrophines, as well as with fragments of these peptides, to a possible therapeutic application is not possible.